In the past two years, we have studied changes in glial cells and myelin that occur in the aging monkeys. We have found that primarily in their white matter, aged animals have an increased number of activated microglia and astrocytes, which release cytotoxic and myelinotoxic factors (such as oxyradicals, cytokines, and complement). We have also detected a loss of frontal lobe subcortical white-matter myelin, which contains altered levels of several myelin proteins and their proteolytic fragments. As oxidation can render proteins dysfunctional and more prone to degradation by proteolytic enzymes, we therefore hypothesize that these changes in white and possibly gray matter are due to inflammation and oxidative stress. Furthermore, we hypothesize that these pathologic changes lead to the cognitive impairment of aged monkeys. To address these hypotheses, that these pathologic changes lead to the cognitive impairment of aged monkeys. To address these hypotheses, our specific aims are the following: 1) To determine levels and localization of cytokines, complement, and oxyradical damage from young, middle-aged, and aged brain and correlate any changes with age and specific cognitive deficits (with Project 1). These experiments will test the hypothesis that factors produced by activated microglia and astrocytes attack the integrity of myelin, neurons, and synapses by causing oxidation or proteolysis of myelin and neuronal proteins. These molecular changes may lead to altered conductivity and to impaired cognition.. 2) To determine the relationship between white matter and gray matter changes and the levels of anti-oxidants. We hypothesize that the aged brain suffers from anti-oxidant deficiency and is thus more vulnerable to oxyradical attacks. 3) To determine in fresh slices of white and gray matter the effects of oxyradicals, cytokines and complement on the myelin proteins (including proteolysis), myelin ultrastructure (with Project 4), and electrophysiology of selected neurons using single cell recordings and conduction velocity measurements (with Project 3). These experiments will test the hypothesis that our observed white matter changes correlate with cognitive deficits. The above investigations represent a fundamental and exciting continuation of our studies aimed to elucidate the mechanism underlying normal brain aging.